Key documents, regulations and other resources relevant to clinical research

The UK policy framework for health and social care research replaces the Research Governance Frameworks (RGF) previously issued in each of the four UK countries. The policy framework sets out principles of good practice in the management and conduct of health and social care research that take account of legal requirements and other standards.

GCP is a set of internationally recognised ethical and scientific quality requirements for designing, conducting, recording and reporting research that involves human participation. Compliance provides public assurance that the rights, safety and wellbeing of participants are respected and protected, and that the data generated are credible and accurate.

Compliance with GCP is a legal obligation in Europe for all trials of investigational medicinal products.

Comprised of 13 core principles, GCP applies to all clinical investigations that can affect the safety and well-being of human participants, particularly clinical trials of investigational medicinal products.

GCP core principles

1

Clinical trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with GCP and the applicable regulatory requirement(s).

2

Before a trial is initiated, foreseeable risks and inconveniences should be weighed against the anticipated benefit for the individual trial subject and society. A trial should be initiated and continued only if the anticipated benefits justify the risks.

3

The rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society.

4

The available non-clinical and clinical information on an investigational product should be adequate to support the proposed clinical trial.

5

Clinical trials should be scientifically sound, and described in a clear, detailed protocol.

6

A trial should be conducted in compliance with the protocol that has received prior institutional review board (IRB)/independent ethics committee (IEC) approval/favourable opinion.

7

The medical care given to, and medical decisions made on behalf of, subjects should always be the responsibility of a qualified physician or, when appropriate, of a qualified dentist.

8

Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s).

9

Freely given informed consent should be obtained from every subject prior to clinical trial participation

10

All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation and verification.

11

The confidentiality of records that could identify subjects should be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).

12

Investigational products should be manufactured, handled, and stored in accordance with applicable good manufacturing practice (GMP). They should be used in accordance with the approved protocol.

13

Systems with procedures that assure the quality of every aspect of the trial should be implemented.

The EU Clinical Trials Directive (EUCTD – 2001/20/EC) sets out how clinical trials investigating the safety or efficacy of a medicinal product in humans must be conducted. It includes medicinal trials with healthy volunteers and small scale or pilot studies.

The Good Clinical Practice (GCP) Directive (2005/28/EC) supplements the EUCTD, strengthening the legal basis for requiring member states to comply with the principles and guidelines of good clinical practice, as set out in the ICH GCP guidelines.

Good Clinical Practice (GCP)

The requirement to conduct all clinical trials in accordance with the internationally recognised principles of GCP, helps to ensure that all UK trials are conducted to the appropriate high standard and that risks to patient volunteers are minimised.

Good Manufacturing Practice

The requirement to manufacture investigational medicinal products to GMP standards ensures that trial participants are not exposed to poor quality or badly prepared medicines.

GCP and GMP inspections and enforcement

Inspections by the MHRA to check that the principles and standards of GCP and GMP are being followed ensures overall quality of UK clinical trials and helps identify non-compliance. If non-compliance persists or inspectors suspect fraud the regulations provide powers of enforcement.

Protection of incapacitated adults

The regulations contain provisions for the protection of adults incapable of giving informed consent, for example, those with advanced Alzheimer’s disease, who should be able to participate in research that relates to their condition. CTIMP studies falling under the Clinical Trial Regulations are unique in English law as the only place where one adult acting in the role of the patient’s personal or professional legal representative may provide proxy consent to study participation on behalf of an adult who lacks the capacity to decide for themselves. The Clinical Trial Regulations are also the only place in English law where consent to trial participation given by a competent adult remains valid if they subsequently lose capacity while on study.

The 2006 no2 amendment to the Clinical Trials Regulations created provisions for RECs to issue an Emergency Waiver of Consent to allow the recruitment of incapacitated adults into CTIMP studies in emergency situations where it would not be safe or feasible to secure consent, such as in cardiac arrest or other acute medical emergencies. In this situation, consent from the patient (if recovered) or their legal representative must be sought as soon as reasonably practicable following the emergency treatment.

Protection of minors

The regulations provide additional protection for a minor who is being considered for a clinical trial, ie a person under the age of 16. They require, among other provisions, that:

The REC considering the trial must receive advice on the relevant field of paediatric care

A person with parental responsibility or legal representative must give informed consent and may withdraw the young person at any time

In relation to the minor himself:

Staff with experience with young people must inform them of the risks and benefits of the trial according to their capacity to understand

The investigator must consider their explicit wish to refuse to participate or to be withdrawn from the trial at any time

The clinical trial must relate directly to an illness from which they suffer or that can only be carried out on minors

The trial must aim to provide some direct benefit for the group of patients involved

Pharmacovigilance arrangements

For all clinical trials of an IMP, systems must be in place for the review of adverse events and processing of serious adverse events, which must be immediately reported to the sponsor, unless identified in the protocol or investigator’s brochure as not requiring immediate reporting.

Investigators and trial sponsors together must record suspected unexpected serious adverse reactions thought to be caused by the trial medicine and report them to the MHRA. Assessors at the MHRA can identify safety signals from these reports indicating when trial participants are at increased risk and the trial should be modified or stopped.

The directive also requires each of the 25 member states to enter safety data from trials in their country into a single European pharmacovigilance database which will be a resource to the UK for early identification of safety signals derived from the clinical trials.

The Human Tissue Act 2004 repealed and replaced the Human Tissue Act 1961, the Anatomy Act 1984 and the Human Organ Transplants Act 1989 as they related to England and Wales, and the corresponding orders in Northern Ireland. The Human Tissue Authority regulates the removal, storage, use and disposal of human bodies, organs and tissue.

The Declaration of Helsinki was developed by the World Medical Association as 'a statement of ethical principles for medical research involving human subjects, including research on identifiable human material and data' (Para 1, Declaration of Helsinki).

Most clinical research requires the processing and/or storage of personal and sensitive information. The General Data Protection Regulation (GDPR) legislates for the control and protection of personal information relating to living individuals including both facts and opinions about the individual. It is vital that all University research and researchers comply with the act and process/store all personal information in accordance with it.

Research studies involving adults aged 16 or over who lack capacity must comply with the Mental Capacity Act 2005. This includes persons with dementia, learning disabilities, mental health problems, stroke or head injuries who may lack capacity to make certain decisions, including consenting to participate in a research study. The act does not apply to studies falling under the Clinical Trials Regulations (CTIMPs).

Any research involving a person lacking capacity that would otherwise have required consent from participants may only be lawfully carried out if an NHS REC in England or Wales has given a favourable opinion. This includes research that would otherwise fall outside the remit of an NHS REC. The REC can only approve the research if it meets the following criteria:

It is connected to an impairing condition affecting the incapacitated patient or its treatment

Research of equal effectiveness cannot be carried out if confined to participants with capacity

The research must have the potential to benefit the patient without imposing a disproportionate burdenor

It must provide knowledge of the causes or treatment of others with the same condition, and involve negligible risk to the incapacitated patient, not interfere significantly with their freedom of action or privacy, or be unduly invasive or restrictive.

The MCA also includes provisions for the REC to issue an emergency waiver of consent to allow the recruitment of adults lacking capacity into emergency studies where the patient is incapacitated and it would not be feasible or safe to attempt to consult them on their inclusion in the study. In such cases, the adult patient could be incapacitated because they are unconscious, acutely confused or intoxicated or because they are experiencing shock, severe anxiety, terror or severe pain etc. In such cases, consultee advice must be sought or the patient consented to continued study participation as soon as is reasonable practicable after the emergency has passed.

The current regulatory framework in the UK/EU allows for a range of risk-adapted approaches that may simplify the processes for initiating and conducting some clinical trials. These adaptations are largely related to how much is known about the investigational medicinal product (IMP), and are based on the marketing status of the IMP and standard medical care. Using a simple categorisation of three risk types (safety risks, risk related to participant rights and risk to reliability of results), it is possible to highlight, particularly for lower risk trials, where simplification is possible.

The use of genetically modified organisms (GMOs) in clinical research, usually in the form of vaccines or gene therapy agents (and otherwise known as Advanced Therapy Medicinal Products (ATMPs)), requires: